Deep Sequencing of Relapse and Refractory Hodgkin Lymphoma Genomes: A Study of Tumor Biology and Evolution

复发和难治性霍奇金淋巴瘤基因组的深度测序：肿瘤生物学和进化的研究

• 批准号: 10351582
• 负责人: Felicia Gomez
• 金额: $ 19.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351582
• 关键词: Address; Affect; Aftercare; Architecture; Automobile Driving; B-Lymphocytes; Bioinformatics; Biological Markers; Biology; Cancer Biology; Cells; Clinical; Collection; DNA; Data; Development; Diagnosis; Disease; Disease Outcome; Evolution; Genes; Genome; Genomics; Goals; Heterogeneity; Hodgkin Disease; Location; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Methodology; Methods; Molecular; Monitor; Morphology; Mutate; Mutation; Mutation Detection; Needs Assessment; Newly Diagnosed; Normal tissue morphology; Outcome; Pathway interactions; Patients; Plasma; Population; Prediction of Response to Therapy; Predictive Factor; Primary Neoplasm; Prognosis; Reagent; Recurrence; Reed-Sternberg Cells; Refractory; Relapse; Research; Resistance; Risk Assessment; Salvage Therapy; Sampling; Signal Transduction; Somatic Mutation; Source; Statistical Methods; Techniques; Technology; Testing; Therapeutic; Training; Tumor Biology; Universities; Variant; Washington; Western World; anticancer research; biomarker identification; cancer cell; cancer genomics; cancer type; cell free DNA; cell type; clinically relevant; cohort; deep sequencing; design; exome; exome sequencing; experimental study; genome-wide; improved; innovation; large datasets; lymph nodes; medical schools; mutational status; new therapeutic target; next generation sequencing; predictive marker; programs; standard of care; targeted treatment; therapy resistant; tool; treatment response; tumor; tumor microenvironment

Hodgkin lymphoma (HL) accounts for ten percent of all lymphomas in the western world and remains a substantial clinical problem. Relapsed and refractory (R/R) HL presents a particularly critical unmet clinical need because approximately 25% of HL patients will be refractory to the standard of care or will relapse while receiving treatment, and the overall survival of R/R HL patients is ~50%. New targeted treatment options and improved risk assessment are needed to improve the therapeutic options for these patients. HL is defined by a rare malignant B cell (Hodgkin-Reed-Sternberg , HRS cells) that occupies a small fraction of the tumor microenvironment. Despite many advances in next generation sequencing technologies, the identification of somatic variants in cancers characterized by rare cell populations remains technically and analytically challenging. These obstacles have resulted in a limited number of studies that have used high throughput genome-wide technologies to characterize the genomic landscape of newly diagnosed HL, and far fewer have attempted to use these technologies to address the genomic landscape of R/R HL. Here, we address this shortfall by asking three questions: 1) Can ultra-deep genome-wide sequencing, paired with analysis and filtering strategies optimized for low VAF variants identify somatic variants driving treatment resistance in R/R HL? 2) Can we use somatic mutation status in a large cohort of newly diagnosed and R/R HL to identify genes that are predictive of response to therapy? 3) Can somatic mutations identified in genomic and/or cell free DNA describe clonal heterogeneity among HRS cells and can cell free DNA serve as biomarker of HL at diagnosis or relapse? This research will be broadly impactful because: 1) it will describe the genomic landscape of R/R HL and will identify biomarkers that are predictive of poor response to treatment; 2) it will begin to address the relationship between clonal architecture in HL, disease outcome, and prognosis; 3) it will further define cfDNA as a suitable target for HL disease monitoring By completing this proposal Dr. Felicia Gomez will gain advanced training in genomics, bioinformatics, lymphoma biology, and cancer biology in general. This proposal takes advantage of the cutting edge genomics and cancer research at Washington University School of Medicine (WUSM). WUSM is an ideal location to complete the experiments and training described in this proposal. Dr. Gomez is a well-trained scholar who is poised to develop a program of research that will be innovative and responsive to the need for diversity in the biomedical workforce. When Dr. Gomez transitions to independence she will continue to focus on cancer genomics and will broaden her research to address the interactions between somatic and germline variation and how this interaction affects the development and progression of lymphoma and other malignancies.

霍奇金淋巴瘤 (HL) 占西方世界所有淋巴瘤的百分之十，并且仍然是一种 实质性的临床问题。复发难治性 (R/R) HL 是一个特别关键的未满足的临床问题 需要，因为大约 25% 的 HL 患者难以接受标准治疗或在治疗期间会复发 接受治疗，R/R HL 患者的总生存率约为 50%。新的针对性治疗方案和 需要改进风险评估来改善这些患者的治疗选择。 HL 定义为 占肿瘤一小部分的罕见恶性 B 细胞（Hodgkin-Reed-Sternberg，HRS 细胞） 微环境。尽管下一代测序技术取得了许多进展，但 以稀有细胞群为特征的癌症的体细胞变异在技术和分析上仍然存在 具有挑战性的。这些障碍导致使用高通量的研究数量有限 全基因组技术来表征新诊断的 HL 的基因组景观，但很少有 尝试使用这些技术来解决 R/R HL 的基因组景观。在这里，我们解决这个问题 通过提出三个问题来弥补不足：1）能否进行超深度全基因组测序，并结合分析和 针对低 VAF 变异优化的过滤策略可识别导致 R/R 治疗耐药的体细胞变异 HL？ 2) 我们能否利用大量新诊断和 R/R HL 的体细胞突变状态来识别基因 可以预测治疗反应吗？ 3) 能否在基因组和/或无细胞中鉴定体细胞突变 DNA 描述了 HRS 细胞之间的克隆异质性，无细胞 DNA 可以作为 HL 的生物标志物吗？ 诊断还是复发？这项研究将产生广泛的影响，因为：1）它将描述基因组 R/R HL 的概况，并将识别预测治疗反应不佳的生物标志物； 2）它会 开始解决 HL 克隆结构、疾病结果和预后之间的关系； 3）它会 进一步将 cfDNA 定义为 HL 疾病监测的合适目标 通过完成这项提案，Felicia Gomez 博士将获得基因组学、生物信息学、 淋巴瘤生物学和一般癌症生物学。该提案利用了最先进的基因组学 以及华盛顿大学医学院 (WUSM) 的癌症研究。 WUSM 是一个理想的地点 完成本提案中描述的实验和训练。戈麦斯博士是一位训练有素的学者 准备制定一项研究计划，该计划将具有创新性并响应多样化的需求 生物医学劳动力。当戈麦斯博士过渡到独立时，她将继续关注癌症 基因组学，并将扩大她的研究范围，以解决体细胞变异和种系变异之间的相互作用 以及这种相互作用如何影响淋巴瘤和其他恶性肿瘤的发生和进展。